The vast majority of prostate Cancer (PCa) are histologically classified as adenocarcinoma (AdenoCa), characterized by gland formation and expression of luminal markers androgen receptor (AR) and prostate specific antigen (PSA). It is recognized that some cases of PCa are indolent and require no treatment while others can be treated by local therapies. Advanced PCa is treated by hormonal therapy which eventually fails and progresses to castration resistant PCa (CRPC). Some of the recurrent tumors do not form glands or express luminal markers and are known as small cell neuroendocrine carcinoma (SCNC). Abiraterone and Enzalutamide have recently been approved for CRPC but disease resistance develops quickly. A multi-institutional team has been assembled to biopsy metastatic PCa from 300 men who have failed both conventional and second-line hormonal therapies. From the initial 150 cases, we discovered that some tumors maintain the histology of AdenoCa, while 15% of the tumors have SCNC histology. 30% of the tumors have an intermediate histology which we have named CYBAC (Cytologically Bland Aggressive Carcinoma). While SCNC and CYBAC have uniformly poor prognosis (median survival 6-9 months), patients with metastatic AdenoCa have highly variable outcomes. The novel disease biology poses challenges to clinicians and the research community. The proposal attempts to address some of the most urgent clinical issues with the following specific aims: Aim 1. Identify biomarkers that predict the prognosis of patients with metastatic AdenoCa: We will determine if Gleason grading, which is the best predictor of clinical outcome for primary PCa, can predict the outcome of men with metastatic AdenoCa. We will also determine if certain immunohistochemistry (IHC)-based biomarkers can be used to predict outcome in these patients. Aim 2. Establishing diagnostic criteria for the newly identified PCa histologic variant CYBAC: We have established histologic criteria for the newly identified CYBAC. To help pathologists diagnose this disease entity with confidence, we will establish IHC profile of CYBAC to complement the histology criteria.